CHARACTERIZATION OF THE N-ACETYLGLUTAMATE SYNTHASE KNOCKOUT MOUSE, A NOVEL MODEL OF HYPERAMMONEMIA

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Abstract

All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-L-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. NCG and L-citrulline (Cit) were used to rescue the NAGS knockout homozygous (Nags-/-) pups and the rescued animals were characterized. This regimen has allowed for normal development, apparent health, and reproduction. Interruption of this rescue intervention resulted in the development of severe hyperammonemia and death within 48 hours. We have developed a home cage behavioral system that allows to monitor and analyze the chronology of animal behaviors during healthy and hyperammonemic states. Data collected from this study reveals that mice decrease their normal activity around 12 hours and become severely lethargic by 20 hours following NCG withdrawal. Understanding the chronology of hyperammonemia will aid in future studies to discover neuro-protective drugs for treating hyperammonemia. This mouse model will also allow studies of the pharmacokinetics and pharmacodynamics of NCG, much of which is still unknown. Understanding how NCG is transported into cells and then cleared is clinically relevant and can potentially lead to more efficient administration of this drug. We conclude that a novel NAGS deprived mouse model has been developed which can be rescued by NCG and Cit and reared to reproduction and beyond. This biochemically salvageable mouse model recapitulates the clinical phenotype of proximal urea cycle disorders and can be used as a reliable model of induced hyperammonemia by manipulating the administration of the rescue compounds.